title: Conformational selection in glycomimetics: human galectin-1 only recognizes syn-Ψ-type conformations of β-1,3-linked lactose and its C-glycosyl derivative.
abstract: The human lectin galectin-1 (hGal-1) translates sugar signals, that is, β-galactosides, into effects on the level of cells, for example, growth regulation, and has become a model for studying binding of biopharmaceutically relevant derivatives. Bound-state conformations of Galβ-C-(1→3)-Glcβ-OMe (1) and its βGal-(1→3)-βGlc-OMe disaccharide parent compound were studied by using NMR spectroscopy (transferred (TR)-NOESY data), assisted by docking experiments and molecular dynamics (MD) simulations. The molecular recognition process involves a conformational selection event. Although free C-glycoside access four distinct conformers in solution, hGal-1 recognizes shape of a local minimum of compound 1, the syn-Φ/syn-Ψ conformer, not the structure at global minimum. MD simulations were run to explain, in structural terms, the observed geometry of the complex.
authors.affiliation: Discovery Chemistry Research and Technologies, Centro de Investigación Lilly, Avenida de la Industria 30, 28108 Alcobendas, Madrid (Spain).
authors.forename: Paloma
authors.initials: P
authors.lastname: Vidal
authors.forename: Virginia
authors.initials: V
authors.lastname: Roldós
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Fernández-Alonso
authors.forename: Boris
authors.initials: B
authors.lastname: Vauzeilles
authors.forename: Yves
authors.initials: Y
authors.lastname: Bleriot
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Cañada
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Juan Félix
authors.initials: JF
authors.lastname: Espinosa
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
mesh_terms: D037483:Galectin 1 / Q000737:chemistry / Q000378:metabolism*; D054794:Glycomics; D006027:Glycosides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007785:Lactose / Q000737:chemistry*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D013379:Substrate Specificity
chemical_list: D037483:Galectin 1; D006027:Glycosides; D007785:Lactose
keywords: NMR spectroscopy; conformation analysis; glycoconjugates; molecular modeling; structure-activity relationships